The major ligand-receptor systems involved in uptake of the intracellular pathogens Trypanosoma cruzi, Salmonella typhimurium, and Toxoplasma gondii by phagocytic cells were examined. For T. cruzi, incubation of infective typomastigotes in normal human serum does not lead to parasite lysis but markedly enhances entry into macrophages and monocytes. This enhancement is due to deposition of complement component C1q on the parasite, and the additional interaction of C1q with fibronectin bound to the parasite. C3 fragments play no role in enhancing internalization. Trypomastigotes are thus targeted to cells bearing large numbers of fibronectin and C1q receptors, of which fibroblasts and epithelial cells are the prototype. Salmonella typhimurium, and other Salmonella species attach to and enter phagocytic cells via receptors for C3 fragments. Mannose binding protein, an acute phase reactant in serum which binds to mannose on selected microbial surfaces, is a direct opsonin for Salmonella containing mannose in the lipopolysaccharide. Mannose binding protein also enhances complement activation on the surface of mannose bearing strains. Toxoplasma gondii attachment and entry into macrophages is augmented by fibronectin. Furthermore, fibronectin binds in specific fashion to the parasite. A surface iodinatable 16-18kd molecule on the tachyzoite, shown to be anchored to the parasite cytoskelton, has been purified to homogeneity. This role of this molecule in binding fibronectin and in cell entry is under investigation.